Clinical outcomes of endoscopic submucosal dissection for large pedunculated colorectal carcinoma: A retrospective multicenter study

Abstract Objectives Complete en‐bloc resection of pedunculated colorectal carcinoma is necessary for a proper pathological diagnosis. However, due to poor visibility, large pedunculated colorectal carcinomas are difficult to snare and resect en‐bloc using endoscopic resection or polypectomy. Additionally, the bleeding risk of large pedunculated colorectal carcinomas is relatively high. We aimed to assess the feasibility and safety of endoscopic submucosal dissection for large pedunculated colorectal carcinomas. Methods We conducted a retrospective multicenter cohort study to assess 36 consecutive patients with 36 large pedunculated colorectal carcinomas who underwent endoscopic submucosal dissection and evaluated the outcomes of endoscopic submucosal dissection. Furthermore, patients were divided into two groups according to the procedure time, and the factors related to the procedure time were assessed. Results The mean tumor size was 34.1 ± 9.9 mm. The en‐bloc, complete en‐bloc, and curative resection rates were 97% (35/36), 97% (35/36), and 81% (29/36), respectively. The rate of severe bleeding during the procedure was 11% (4/36); however, it could be controlled endoscopically in all patients. The rate of intraoperative perforation and delayed bleeding was 0% (0/36). Delayed perforations occurred in one patient that required surgery. A long procedure time was correlated with the location of the flexure and poor endoscope operability. No recurrence was observed in any patient. None of the patients died of colorectal carcinoma. Conclusions Our results showed the feasibility and safety of endoscopic submucosal dissection for large pedunculated colorectal carcinomas.


INTRODUCTION
Polypectomy is a standard procedure widely used for the treatment of pedunculated colorectal polyps. Postpolypectomy bleeding (PPB) is one of the most common complications of polypectomy. The risk of PPB after resection of large pedunculated polyps is high. [1][2][3] Large colorectal polyps have a high risk of submucosal invasive carcinoma. 4,5 Haggitt et al. stratified the levels of submucosal invasion of pedunculated colorectal carcinomas (CRCs) from 0 to 4 and reported a low risk of metastasis or local recurrence at levels below 4. 6 Matsuda et al. reported that the incidence of lymph node metastasis was lower in patients with head invasion than in those with stalk invasion. 7 Therefore, complete en-bloc resection should be performed for large pedunculated CRCs following an appropriate pathological diagnosis. However, due to poor visibility, large pedunculated CRCs are difficult to snare and resect en bloc using endoscopic mucosal resection (EMR) or polypectomy.
Endoscopic submucosal dissection (ESD) can be performed for complete en-bloc resection regardless of tumor size and location. 8 Additionally, ESD has the advantage of being able to visualize submucosal tissue and blood vessels directly and achieve hemostasis in blood vessels during the procedure.
Colorectal ESD is already a commonly performed procedure worldwide, and the feasibility and safety of this procedure have previously been proven. 9 Recently, several studies have reported the feasibility and safety of ESD for large pedunculated colorectal polyps [10][11][12][13][14] ; however, most of these studies were case reports, and the evidence is still insufficient. Therefore, we aimed to assess the feasibility and safety of ESD for large pedunculated CRC and the factors related to procedure time.

Patients
This was a multicenter, retrospective cohort study comprising an academic hospital and 24 community hospitals with varying levels of experience in colorectal ESD. We performed ESD for 3937 colorectal neoplasms (CRNs) at the Hiroshima GI Endoscopy Research Group between January 2008 and December 2018 (1259 CRNs of retrospective registration between January 2008 and March 2014 and 2678 CRNs of prospective registration between December 2013 and December 2018). Among the CRNs, 36 large pedunculated CRCs were included in the present study and retrospectively analyzed. ESD for a large pedunculated CRC was performed as an alternative treatment to EMR or polypectomy at the endoscopist's discretion for the following three reasons: first, technical difficulty of snar-ing for en-bloc resection due to the large tumor size and poor visibility. Second, high risk of bleeding due to the thick stalk, and lastly, the difficulty of prophylactic hemostasis due to the short stalk or poor visibility.
This study was performed in accordance with the ethical standards of the Declaration of Helsinki and its later amendments. The study protocol was reviewed and approved by the institutional review boards of each participating center and registered as UMIN000016197 (Institutional Review Board registration date: January 14, 2015). Written informed consent was obtained from the patients.

Histopathological assessment
Histopathological assessment was performed according to the 2019 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 15 and the World Health Organization classification system. 16 The pathological diagnosis was Tis carcinoma and submucosal invasive (T1) carcinoma. Complete en-bloc resection was defined as a pathologically identified en-bloc resection with negative horizontal and vertical margins. Curative resection was defined based on the 2019 JSCCR curative criteria (negative vertical margin, papillary/tubular adenocarcinoma or medullary carcinoma, negative lymphovascular invasion, submucosal invasion depth <1000 µm, and budding grade 1). 17 Submucosal invasion depth was assessed according to the Japanese criteria. 15

ESD procedure
A 10% glycerin solution containing 0.4% sodium hyaluronate (MucoUp; Johnson & Johnson) and a small amount of indigo carmine (indigo carmine/hyaluronate/glycerol: 0.2/10/10 ml) was used for submucosal injection. DualKnife (Olympus), DualKnife J (Olympus), ITknife nano (Olympus), or SBknife Jr (Sumitomo Bakelite) was used as appropriate for each patient at the endoscopist's discretion. Multiple devices were used, depending on the situation. During a submucosal dissection, prophylactic hemostasis was applied as appropriate while visualizing the blood vessels of the submucosal tissue in the stalk. At the end of the procedure, the exposed vessels on the resected ulcer were coagulated using hemostatic forceps. Hemostatic clips were also used, depending on the situation.

Evaluation
Clinicopathological characteristics (sex, age, use of antithrombotic agents, tumor location, local difficulty, tumor size,degree of submucosal fibrosis,and pathological diagnosis) and treatment outcomes were assessed. Treatment outcomes; including procedure time, endoscope operability, en-bloc resection, complete en-bloc resection, curative resection, bleeding during the procedure, delayed bleeding, intraoperative perforation, delayed perforation, additional surgical resection; operator; and endoscopic device, were evaluated. Moreover, we divided the patients into two groups (long procedure time and short procedure time) according to the procedure time and assessed the factors related to procedure time. Additionally, local or metastatic recurrence, prognosis, characteristics, and treatment outcomes of patients with T1 CRC were examined.
The degree of submucosal fibrosis was classified into three types (F0, no fibrosis; F1, mild fibrosis; and F2, severe fibrosis) based on previous reports. 18 Poor endoscope operability refers to paradoxical endoscope movement, poor control with adhesions, and passive movements of the lesion or the endoscope resulting from the patient's respiration or heartbeats. 19 Severe bleeding was defined as bleeding that required multiple coagulation (≥ 10 times) during the procedure. 20 Delayed bleeding was defined as ≥ 2 g/dl decrease in hemoglobin levels compared to the preoperative level, apparent bleeding, or massive melena after the procedure. 21 Experts were defined as endoscopists who had performed more than 80 cases of colorectal ESD. 22 The procedure time of ESD was defined as the time from the beginning of the submucosal injection until the complete resection of the lesion.

Statistical analysis
Quantitative data are presented as the mean ± standard deviation or percentage. Continuous variables were analyzed using Student's t-test. Categorical variables were analyzed using Fisher's exact test or the chisquared test. Statistical significance was set at p < 0.05. The JMP statistical software (version 15.0.0; SAS Institute) was used for all statistical analyses. Table 1 shows the clinicopathological characteristics of the enrolled patients and their tumors. The tumors were most often located in the left colon (56% [20/36]). The rate of tumors located at the flexure was 11% (4/36), and the rate of tumors straddling a fold was 28% (10/36). The mean tumor size was 34.1 ± 9.9 mm. The rate of T1 CRC was 25% (9/36). Four (11%) patients had head invasion, none had submucosal inva-TA B L E 1 Clinicopathological characteristics.

Factors related to procedure time
The median procedure time was 40 min. The lesions were divided into two groups based on the median procedure time: long (<40 min) and short (≥40 min). The short and long procedure time groups comprised 20 and 16 patients, respectively. Tables 3 and 4 display a comparison of clinicopathological characteristics and ESD outcomes between the two groups. The rate of tumors located at the flexure was significantly higher in the long procedure time group (25%, 4/16) than in the short procedure time group (0%, 0/20; p = 0.0309). The mean tumor size was larger in the long procedure time group (37.5 ± 10.3 mm) than in the short procedure time group (31.4 ± 8.9 mm), but there was no significant difference in the mean tumor size between the two groups (p = 0.0659). The rate of poor endoscope operability was significantly higher in the long procedure time group (62%, 10/16) than in the short procedure time group (10%, 2/20; p = 0.0014). There were no significant differences in other clinicopathological characteristics or ESD outcomes between the two groups.

Characteristics of large pedunculated T1 CRC
Characteristics of the nine patients with T1 CRC are shown in Table 5. Of the nine patients, four had head invasions, and five had submucosal invasions of ≥1000 µm. Most tumors were located in the sigmoid colon (89%, 8/9). The minimum and maximum tumor sizes were 20 and 50 mm, respectively. The en bloc and complete en-bloc resection rates were 100% (9/9). The curative resection rate was 33% (3/9 patients). Five patients showed lymphovascular invasion. One patient had a tumor budding grade 2. One patient had a mucinous histology. Additional surgical resection was performed in seven patients. In patient 3, an additional surgical resection was performed because of mucinous histology in the invasive portion. No local or metastatic recurrence was observed in any patient. None of the patients died of CRC (observation period: 47 months).

DISCUSSION
Our data showed that the outcomes of ESD for large pedunculated CRCs were good, without severe complications. As mentioned previously, the colorectal ESD procedure is well established. 9 There have been several studies on ESD for large pedunculated colorectal polyps. [10][11][12][13][14] Recently, a multicenter retrospective study was reported 14 ; however, most previous studies were conducted on a small number of patients, and the evi- dence is still insufficient. Our results are consistent with those of previous studies. Additionally, we assessed factors related to procedure time. We found that a long procedure time was correlated with the location at the flexure and poor endoscope operability. To our knowledge, this is the first study to discuss the factors related to ESD procedure time for large pedunculated CRC. Our results demonstrated the feasibility and safety of ESD for large pedunculated CRC. We previously assessed the long-term outcomes for pedunculated T1 CRCs after endoscopic resection or surgical resection and reported that the risk of lymph node metastasis, based on the JSCCR diagnostic criteria, should be evaluated after endoscopic resection for pedunculated T1 CRC. 23 In addition, additional surgery should be considered in patients at high risk of lymph node metastasis. 23 Therefore, complete en-bloc resection should be performed for large pedunculated CRC, and appropriate pathological diagnosis should be performed to assess the risk of lymph node metastasis. However, due to poor visibility, large pedunculated CRCs are difficult to snare and resect en bloc using EMR or polypectomy.
An ESD can be performed for complete en-bloc resection regardless of the tumor size and location. 8 Choi et al. 10 retrospectively compared the feasibility of ESD and polypectomy for giant pedunculated polyps and reported that the en-bloc resection rate was 100% (23/23) in the ESD group and 90% (18/20) in the polypectomy group regardless of whether the endoscopists judged that it could be possible. In this study, the rates of en-bloc resection and complete en-bloc resection were 97% (35/36) each, similar to that reported previously. 10,14 The rates of en-bloc resection and complete en-bloc resection for T1 CRC were 100% (9/9), which was also good. Additionally, there was no local or metastatic recurrence in any of the patients, and their prognoses were good. Furthermore, complete en-bloc resection using ESD was possible for large pedunculated CRCs, including T1 CRC. Appropriate pathological diagnosis and evaluation of the risk of lymph node metastasis were also possible. In ESD, submucosal dissection is performed while visualizing the submucosal layer. Therefore, even in cases of stalk invasion, the tumor could be removed without tumor remnant by visualizing the tumor mass and dissecting the submucosal layer under the tumor. Therefore, our results showed that ESD is an effective treatment for large pedunculated CRC regarding complete en-bloc resection.
PPB is one of the most common complications of polypectomy. The risk of PPB after resection of large pedunculated polyps is high because large feeding vessels traverse the stalk to supply the head of the polyp. 1 Soh et al. 3 reported that polyp size ≥ 20 mm and stalk diameter ≥ 4 mm increased the risk of immediate PPB after resectioning large pedunculated polyps. In endoscopic resection of pedunculated polyps, especially in cases with large tumor sizes, it is necessary to manage bleeding with effective preventive methods.
Injection (adrenaline and epinephrine) 24 and mechanical (endoloop and hemostatic clips) 3,25,26 therapies have been developed as bleeding prevention methods after polypectomy for pedunculated polyps, and their efficacies have been reported. However, the application of an endoloop can be challenging, particularly for polyps with a large head or short stalk, because endoloops have a lower expansible force and stiffness. Additionally, prophylactic hemostatic clips might not completely cover the stalk of large pedunculated polyps and stop blood flow in the stalks completely when the stalk is thick. On the other hand, ESD has the advantage of being able to visualize submucosal tissue and blood vessels directly and apply hemostasis to blood vessels during the procedure. Choi et al. 10 reported that the rate of intraoperative bleeding requiring endoscopic hemostasis was higher with polypectomy (15%, 3/20) than with ESD (4.3%, 1/23). Additionally, they reported no cases of delayed bleeding after ESD (0%, 0/23). Chiba et al. 14 evaluated the feasibility of ESD for large pedunculated polyps with wide stalks in a retrospective multicenter study and reported no cases of delayed bleeding after ESD (0%, 0/29). In our study, there were no patients with delayed bleeding after ESD (0%, 0/36), similar to previous studies. 10,14 In contrast, the rate of severe intraoperative bleeding was 11% (4/36 patients). This result might be due to the large tumor size (mean, 34.1 mm), thick stalk, and the presence of vessels. However, it could be controlled endoscopically in all patients. Therefore, our results show that ESD is an effective treatment for large pedunculated CRC in terms of bleeding because prophylactic hemostasis could be applied as appropriate while visualizing the blood vessels of the submucosal tissue in the stalk during a submucosal dissection.
In this study, the mean procedure time was 49.9 ± 39.1 min, and the median procedure time was 40 min, similar to the previous study. 10 In this study, the rate of tumors located at the flexure and poor endoscope operability were significantly higher in the long procedure time group than in the short procedure time group. In the long procedure time group, delayed perforation occurred in one patient. The polyp was a 50 mm-sized Tis carcinoma located at the flexure of the sigmoid colon. Bleeding during the procedure was severe, and the muscle layer was severely in traction. This could have caused the delayed perforation. In such cases, endoscopic closure of the ulcers may be effective in preventing delayed perforation. Poor endoscope operability during ESD was reported as a significant independent predictor of perforation. 19 Lesion located at the colonic flexures was reported to be a strong indicator of longer procedure time and a significant risk factor for the incidence of perforation. 27 Our results were consistent with the previous reports. 19,27 However, the outcomes were equally good in the long procedure time group. Our results showed that ESD is an effective treatment for large pedunculated CRC, even in difficult cases. There is a possibility that ESD for large pedunculated CRC could be performed more safely and effectively using different devices (single-balloon overtubes, 28 scissorstype knives, 29,30 insulated-tip knives, etc.), depending on the size and situation. However, ESD has cost, hospitalization, and procedure time disadvantages and should be performed in selected cases where EMR or polypectomy is difficult.
Our study had some limitations. First, it was a multicenter, retrospective cohort study; however, the sample size was relatively small. A prospective study with a larger number of patients should be conducted in the near future to confirm our results. Second, we lacked information on the thickness and length of the stalks and were, therefore, unable to evaluate them. Future studies should consider not only the tumor size but also the thickness and length of the stalk. Third, we lacked a control group and were unable to compare ESD with EMR and polypectomy. Forth, ESD was selected as an alternative treatment to EMR or polypectomy at the endoscopist's discretion, and selection bias exists. In conclusion, ESD outcomes for large pedunculated CRC were good and without severe complications.Our results show that ESD is an effective and safe treatment for large pedunculated CRC.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declared ST is the president of JGES.

DATA AC C E S S I B I L I T Y S TAT E M E N T
All the data used to support the findings of this study are included in this article.